Diastereoselective Synthesis of Biologically Active Cyclopenta[b]indoles

Abstract

The cyclopenta[b]indole motif is present in several natural and synthetic biologically active compounds, being directly responsible for the biological effects some of them present. We described herein a three step sequence for the synthesis of cyclopenta[b]indoles with a great structural diversity. The method is based on an oxidative Michael addition of suitable indoles on the double bond of Morita-Baylis-Hillman adducts mediated by a hypervalent iodine reagent (IBX) to form β-ketoesters, which were chemoselectively reduced with NaBH4 in THF to give the corresponding β-hydroxy-esters. The diastereoisomeric mixture was then treated with a catalytic amount of triflic acid (20 mol %) to give cyclopenta[b]indoles with overall yields ranging from 8 to 73% (for 2 steps). The acid-catalyzed cyclization step gave the required heterocycles, via an intramolecular Friedel-Crafts reaction, with high diastereoselectivity, where only the trans product was observed. A mechanistic study monitored by ESI-(+)-MS was also conducted to collect evidence about the mechanism of this reaction. The new molecules herein synthesized were also evaluated against a panel of human cancer cells demonstrating a promising antitumoral profile.

Palladium-Mediated Oxidative Annulation of δ-Indolyl-α,β-Unsaturated Compounds toward the Synthesis of Cyclopenta[b]indoles and Heterogeneous Hydrogenation To Access Fused Indolines

“…We have identified various cyclopenta [b]indoles as potential drug candidates, and their antitumoral activities have been confirmed by in vitro biological assays. 36 To expand this study, we needed to prepare a set of cyclopenta [b]indoles possessing electron-withdrawing substituents on the six-membered aromatic ring of the indole and a single substituent on the five-membered aliphatic ring. Previously, we prepared cyclopenta [b]indoles using an acidcatalyzed intramolecular Friedel−Crafts reaction of an intermediate synthesized from an 2-iodoxybenzoic acid oxidation of a Morita−Baylis−Hillman adduct, followed by a Michael addition of an indole.…”

“…Some years ago, we started a research program focused on the discovery of new antitumoral agents. We have identified various cyclopenta­[ b ]­indoles as potential drug candidates, and their antitumoral activities have been confirmed by in vitro biological assays . To expand this study, we needed to prepare a set of cyclopenta­[ b ]­indoles possessing electron-withdrawing substituents on the six-membered aromatic ring of the indole and a single substituent on the five-membered aliphatic ring.…”

Catalyst-Free Conjugate Addition of Indolizines to In Situ-Generated Oxidized Morita–Baylis–Hillman Adducts

“…The exceptionally shorter reaction time observed in these conjugate addition reactions using indolizines as nucleophiles intrigued us since the two previous works with indoles reported longer reaction times (6–12 h) for the same electrophiles under reflux conditions. , Using the experimental conditions developed by us (see Experimental Section), the adduct generated from the indole conjugate addition 9aa was obtained with 75% yield. This yield is comparable to those obtained by Santos et al and Yadav et al (80%) . The fast reaction time observed in the indole conjugate addition does not allow a direct nucleophilicity comparison between indolizine 1a and indole ( 11a ).…”

“…21,28 Using the experimental conditions developed by us (see Experimental Section), the adduct generated from the indole conjugate addition 9aa was obtained with 75% yield. This yield is comparable to those obtained by Santos et al 28 and Yadav et al (80%). 21 The fast reaction time observed in the indole conjugate addition does not allow a direct nucleophilicity comparison between indolizine 1a and indole (11a).…”

Insights into the regioselectivity and diastereoselectivity of the Nazarov cyclization of 3-alkenyl-2-indolylmethanol with tryptophol

“…[6][7][8] Consequently, the synthesis of cyclopentyl indole derivatives has aroused great interest, and many protocols have been developed toward achieving this goal. [9][10][11][12][13] Nazarov cyclization is an effective method for constructing a five-membered cyclopentane skeleton. The currently reported catalytic asymmetric Nazarov reactions mainly use divinyl ketone as a substrate and a strong chiral acid N-triflylphosphoramides as catalyst.…”